The increasingly frequent use of radiation therapy (RT) and systemic chemotherapy (CT) in the treatment of breast carcinoma requires surgical pathologists and cytologists to be familiar with the variable histologic changes initiated by these agents. Both treatment modalities can cause severe epithelial abnormalities, which are difficult to distinguish from carcinoma. The progression or regression of these histologic abnormalities in nonneoplastic breast tissue have not been extensively evaluated. Our study used 120 post-RT biopsy or mastectomy specimens from 117 patients (3 had bilateral carcinoma treated with RT) yielding 120 specimens. The interval from post-RT to biopsy or mastectomy ranged from 1 to 229 months with 25 of the specimens obtained 1 to 12 months after cessation of RT and 95 more than a year post-RT. Twenty-seven specimens were from >6 years after RT. The histologic features of pretreatment and posttreatment specimens were graded (0-3) blindly for each histologic feature to include stromal vascular and fibroblastic changes and epithelial cell changes of the terminal duct lobular unit and extralobular ducts as well as terminal duct lobular unit fibrosis/atrophy. The changes between the pre- and post-RT grades were all statistically significant (P < 0.05) using multiple nonparametric statistical methods and the parametric Student t test. The specimens obtained within the first year post-RT were compared with those from >1 year post-RT, >3 years post-RT, and >6 years post-RT. None of the histologic features evaluated showed significant changes over the various time intervals regardless of the statistical method used. The absence of regression of the radiation-induced histologic changes over time mandates the surgical pathologist be alert to the possibility of RT or CT even without that therapeutic history.